Yang Tianxin, Huang Yuning G, Ye Wenling, Hansen Pernille, Schnermann Jurgen B, Briggs Josephine P
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Am J Physiol Renal Physiol. 2005 Jun;288(6):F1125-32. doi: 10.1152/ajprenal.00219.2004. Epub 2004 Dec 21.
The present study was undertaken to determine whether the severity of renal failure or hypertension in homozygous cyclooxygenase (COX)-2-deficient (COX-2-/-) mice affected by genetic background or gender. COX-2 deletion was introduced into three congenic genetic backgrounds, 129/Sv (129/COX-2-/-), C57/BL6 (C57/COX-2-/-), and BALB/c (BALB/COX-2-/-), by backcrossing the original mixed-background knockout mice with the respective inbred strains for 9 or 10 generations. Evaluation of the severity of hypertension and renal failure was performed in knockout and wild-type mice at the age of 2.5-3.5 mo. Blood pressure measured by tail-cuff plethysmography was significantly elevated in the male 129/COX-2-/- mice (165.8 +/- 9.2 vs. 116 +/- 5.1 mmHg, P < 0.05), and to a much lesser extent in the female 129/COX-2-/- mice (127.4 +/- 3.3 vs. 102.4 +/- 3.3), whereas it was unchanged in the C57- or BALB/COX-2-/- mice regardless of gender. Urinary excretion of albumin, determined by EIA, was remarkably increased in the 129/COX-2-/- (16.4 +/- 4.1 vs. 0.16 +/- 0.043 mg albumin/mg creatinine, P < 0.001), and to a lesser extent in the male C57/COX-2-/- mice (0.595 +/- 0.416 vs. 0.068 +/- 0.019). Albumin excretion was not elevated in the male BALB/COX-2-/- or in female COX-2-/- mice on any of the three genetic backgrounds. Histological analysis showed abundant protein casts, dilated tubules, and infiltration of inflammatory cells in the male 129/COX-2-/- mice, but not in COX-2-/- mice in other strains or gender. However, the presence of small glomeruli in the nephrogenic zone was observed in all strains of COX-2 knockout mice, regardless of genetic background and gender. Therefore, we conclude that the severity of hypertension and renal failure in COX-2-deficient mice is influenced by genetic background and gender, whereas the incomplete maturation of outer cortical nephrons appears to be independent of genetic background effects.
本研究旨在确定纯合环氧化酶（COX）-2缺陷（COX-2-/-）小鼠的肾衰竭或高血压严重程度是否受遗传背景或性别的影响。通过将原始混合背景的基因敲除小鼠与各自的近交系回交9或10代，将COX-2缺失引入三种同源基因背景，即129/Sv（129/COX-2-/-）、C57/BL6（C57/COX-2-/-）和BALB/c（BALB/COX-2-/-）。在2.5至3.5月龄的基因敲除小鼠和野生型小鼠中评估高血压和肾衰竭的严重程度。通过尾套体积描记法测量的血压在雄性129/COX-2-/-小鼠中显著升高（165.8±9.2对116±5.1 mmHg，P<0.05），而在雌性129/COX-2-/-小鼠中升高程度较小（127.4±3.3对102.4±3.3），而在C57-或BALB/COX-2-/-小鼠中，无论性别，血压均无变化。通过酶免疫测定法测定的尿白蛋白排泄在129/COX-2-/-小鼠中显著增加（16.4±4.1对0.16±0.043 mg白蛋白/mg肌酐，P<0.001），在雄性C57/COX-2-/-小鼠中增加程度较小（0.595±0.416对0.068±0.019）。在三种基因背景中的任何一种背景下，雄性BALB/COX-2-/-或雌性COX-2-/-小鼠的白蛋白排泄均未升高。组织学分析显示，雄性129/COX-2-/-小鼠中有大量蛋白管型、肾小管扩张和炎症细胞浸润，但在其他品系或性别的COX-2-/-小鼠中未观察到。然而，在所有品系的COX-2基因敲除小鼠中，无论遗传背景和性别，均观察到肾发生区存在小肾小球。因此，我们得出结论，COX-2缺陷小鼠的高血压和肾衰竭严重程度受遗传背景和性别的影响，而外皮质肾单位的不完全成熟似乎与遗传背景效应无关。
